The role of cellular objectives and selective pressures in metabolic pathway evolution

Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.

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A Critical Role of Glutamine and Asparagine γ-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus

mBio ◽

10.1128/mbio.01179-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 19

Author(s):

Ying Zhu ◽

Tingting Li ◽

Suzane Ramos da Silva ◽

Jae-Jin Lee ◽

Chun Lu ◽

...

Keyword(s):

Cell Proliferation ◽

Cancer Cells ◽

Metabolic Pathway ◽

Tca Cycle ◽

Glutamine Metabolism ◽

Transformed Cells ◽

Oncogenic Virus ◽

Phosphoribosyl Pyrophosphate ◽

Rate Limiting

ABSTRACT While glutamine is a nonessential amino acid that can be synthesized from glucose, some cancer cells primarily depend on glutamine for their growth, proliferation, and survival. Numerous types of cancer also depend on asparagine for cell proliferation. The underlying mechanisms of the glutamine and asparagine requirement in cancer cells in different contexts remain unclear. In this study, we show that the oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV) accelerates the glutamine metabolism of glucose-independent proliferation of cancer cells by upregulating the expression of numerous critical enzymes, including glutaminase 2 (GLS2), glutamate dehydrogenase 1 (GLUD1), and glutamic-oxaloacetic transaminase 2 (GOT2), to support cell proliferation. Surprisingly, cell crisis is rescued only completely by supplementation with asparagine but minimally by supplementation with α-ketoglutarate, aspartate, or glutamate upon glutamine deprivation, implying an essential role of γ-nitrogen in glutamine and asparagine for cell proliferation. Specifically, glutamine and asparagine provide the critical γ-nitrogen for purine and pyrimidine biosynthesis, as knockdown of four rate-limiting enzymes in the pathways, including carbamoylphosphate synthetase 2 (CAD), phosphoribosyl pyrophosphate amidotransferase (PPAT), and phosphoribosyl pyrophosphate synthetases 1 and 2 (PRPS1 and PRPS2, respectively), suppresses cell proliferation. These findings indicate that glutamine and asparagine are shunted to the biosynthesis of nucleotides and nonessential amino acids from the tricarboxylic acid (TCA) cycle to support the anabolic proliferation of KSHV-transformed cells. Our results illustrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway. IMPORTANCE We have previously found that Kaposi’s sarcoma-associated herpesvirus (KSHV) can efficiently infect and transform primary mesenchymal stem cells; however, the metabolic pathways supporting the anabolic proliferation of KSHV-transformed cells remain unknown. Glutamine and asparagine are essential for supporting the growth, proliferation, and survival of some cancer cells. In this study, we have found that KSHV accelerates glutamine metabolism by upregulating numerous critical metabolic enzymes. Unlike most cancer cells that primarily utilize glutamine and asparagine to replenish the TCA cycle, KSHV-transformed cells depend on glutamine and asparagine for providing γ-nitrogen for purine and pyrimidine biosynthesis. We identified four rate-limiting enzymes in this pathway that are essential for the proliferation of KSHV-transformed cells. Our results demonstrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway.

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Cerebrospinal fluid metabolomics in West Syndrome: central role of the serine metabolic pathway

Journal of Translational Science ◽

10.15761/jts.1000223 ◽

2018 ◽

Vol 4 (4) ◽

Cited By ~ 1

Author(s):

Emmanuelle Lagrue ◽

Blandine Madji Hounoum ◽

Clementine Rullier ◽

Christian R Andres ◽

Patrick Emond ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Metabolic Pathway ◽

West Syndrome

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Role of Glucose Metabolic Pathway and Acid-Base Balance in Seizures☆

Reference Module in Neuroscience and Biobehavioral Psychology ◽

10.1016/b978-0-12-809324-5.00120-6 ◽

2017 ◽

Author(s):

J. Velíšková ◽

L. Velíšek

Keyword(s):

Metabolic Pathway ◽

Acid Base Balance ◽

Acid Base ◽

Base Balance

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Distribution of seed dormancy classes across a fire-prone continent: effects of rainfall seasonality and temperature

Annals of Botany ◽

10.1093/aob/mcaa203 ◽

2020 ◽

Author(s):

Justin C Collette ◽

Mark K J Ooi

Keyword(s):

Seed Dormancy ◽

Critical Role ◽

Fire Regimes ◽

Common Species ◽

Functional Responses ◽

Stochastic Disturbance ◽

Climate Gradients ◽

Selective Pressures ◽

Rainfall Seasonality

Abstract Background and Aims Different seed dormancy classes control the timing of germination via different cues. The ecological dissimilarities between classes therefore suggest that they are likely to be subject to different selective pressures, and that species within each class will have diverse functional responses. We aimed to investigate this by assessing how variation in the distribution of dormancy classes is correlated with regional environmental factors, in particular rainfall seasonality and temperature. Additionally, we compare the relative proportions of species with physiological (PD) or physical (PY) dormancy to assess whether dormancy class influences their ability to persist under different rainfall seasonality regimes. Methods Dormancy class was assigned for 3990 species from 281 genera occurring across two climate regions, with either winter or aseasonal rainfall, across temperate fire-prone Australia. All regions have similar vegetation and fire regimes. Using a Bayesian framework, we compared the distribution of dormancy classes across temperature and rainfall climate gradients, for threatened and common species. Key Results A high dormant:non-dormant species ratio highlighted the critical role of dormancy across our study regions. Critically, species showing PD were more likely to be threatened in aseasonal rainfall climate regions. Conclusions Our results support the assumption that dormancy is favoured in environments with stochastic disturbance

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A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin

Scientific Reports ◽

10.1038/s41598-019-52254-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Jong Bong Lee ◽

Masar Radhi ◽

Elena Cipolla ◽

Raj D. Gandhi ◽

Sarir Sarmad ◽

...

Keyword(s):

Oral Administration ◽

Metabolic Pathway ◽

Oral Absorption ◽

Therapeutic Effects ◽

The Novel ◽

Drug Candidates ◽

Biopharmaceutical Properties

Abstract Although adenosine and its analogues have been assessed in the past as potential drug candidates due to the important role of adenosine in physiology, only little is known about their absorption following oral administration. In this work, we have studied the oral absorption and disposition pathways of cordycepin, an adenosine analogue. In vitro biopharmaceutical properties and in vivo oral absorption and disposition of cordycepin were assessed in rats. Despite the fact that numerous studies showed efficacy following oral dosing of cordycepin, we found that intact cordycepin was not absorbed following oral administration to rats. However, 3′-deoxyinosine, a metabolite of cordycepin previously considered to be inactive, was absorbed into the systemic blood circulation. Further investigation was performed to study the conversion of 3′-deoxyinosine to cordycepin 5′-triphosphate in vitro using macrophage-like RAW264.7 cells. It demonstrated that cordycepin 5′-triphosphate, the active metabolite of cordycepin, can be formed not only from cordycepin, but also from 3′-deoxyinosine. The novel nucleoside rescue metabolic pathway proposed in this study could be responsible for therapeutic effects of adenosine and other analogues of adenosine following oral administration. These findings may have importance in understanding the physiology and pathophysiology associated with adenosine, as well as drug discovery and development utilising adenosine analogues.

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